Polymorphic human leukocyte antigen (HLA) molecules (alleles) may influence melanoma progression through regulation of cytokine production and resulting T cell responses. Our previous work has shown that both specific HLA class II alleles and relatively high pre-operative plasma levels of IFN-gamma are independent predictors of melanoma recurrence. In addition, one poor-prognosis HLA class II allele (HLA-DRB1*1101) is associated with both relatively high pre-operative IFN-gamma, levels and melanoma recurrence, suggesting that HLA class II alleles can regulate IFN-gamma, production in melanoma patients. Our preliminary in vitro data suggests that both peptide-specific as well as peptide-non-specific mechanisms can contribute to HLA class II allele-specific regulation of IFN-gamma production. The goal of these studies is to determine how HLA class II alleles and altered cytokine production lead to melanoma progression. We hypothesize that specific HLA class II alleles influence melanoma progression by regulating cytokine production through both peptide-specific as well as peptide-non-specific mechanisms. In this project, we will determine if HLA class II alleles are prognostic markers in a large cohort of patients with early-stage melanoma (Specific Aim 1); we will evaluate a related set of potential prognostic markers mechanistically-linked to HLA class II and IFN-gamma in a subset of this same patient population (Specific Aim 2); and we will evaluate potential allele-specific mechanisms regulating IFN-gamma production by measurement of in vitro IFN-gamma production by HLA-typed melanoma patient lymphocytes (Specific Aim 3). HLA class II alleles, IFN-gamma levels and the additional markers selected for investigation represent a group of mechanistically-linked, potentially important melanoma prognostic markers. Coordinated evaluation of these markers and their mechanisms will provide important information about their contributions to melanoma prognosis. These data will be incorporated into selection of patients for adjuvant therapies and used to prioritize markers selected for incorporation into upcoming clinical trials.